Method of treating a CNS injury with a PDE1 inhibitor

ABSTRACT

The subject matter generally relates to methods of treatment and/or prophylaxis of CNS diseases, disorders, and/or injuries. In one aspect, the subject matter relates to inhibitors of phosphodiesterase 1 (PDE1) as neuroprotective agents and/or neural regenerative agents. In a further aspect, the subject matter relates to individuals that are at risk for the development of CNS disease or disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application 61/799,603, filed on Mar. 15, 2013, the contents of which are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The field generally relates to methods of treatment and/or prophylaxis of CNS diseases, disorders, and/or injuries. In one aspect, the field relates to inhibitors of phosphodiesterase 1 (PDE1) as neuroprotective agents and/or neural regenerative agents. In a further aspect, the field relates to prevent the development of a CNS disease or disorder in an individual at risk for the development of a CNS disease or disorder.

BACKGROUND OF THE INVENTION

Eleven families of phosphodiesterases (PDEs) have been identified but only PDEs in Family I, the Ca2+-calmodulin-dependent phosphodiesterases (CaM-PDEs), which are activated by the Ca2+-calmodulin and have been shown to mediate the calcium and cyclic nucleotide (e.g. cAMP and cGMP) signaling pathways. The three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed in central nervous system tissue. PDE1A is expressed throughout the brain with higher levels of expression in the CA1 to CA3 layers of the hippocampus and cerebellum and at a low level in the striatum. PDE1A is also expressed in the lung and heart. PDE1B is predominately expressed in the striatum, dentate gyrus, olfactory tract and cerebellum, and its expression correlates with brain regions having high levels of opaminergic innervation. Although PDE1B is primarily expressed in the central nervous system, it may be detected in the heart. PDE1C is expressed in olfactory epithelium, cerebellar granule cells, striatum, heart, and vascular smooth muscle.

Neurogenesis is a vital process in the brains of animals and humans, whereby new nerve cells are continuously generated throughout the life span of the organism. The newly born cells are able to differentiate into functional cells of the central nervous system and integrate into existing neural circuits in the brain. Neurogenesis is known to persist throughout adulthood in two regions of the mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus. In these regions, multipotent neural progenitor cells (NPCs) continue to divide and give rise to new functional neurons and glial cells (for review Gage 2000). It has been shown that a variety of factors can stimulate adult hippocampal neurogenesis, e.g., adrenalectomy, voluntary exercise, enriched environment, hippocampus dependent learning and antidepressants (Yehuda 1989, van Praag 1999, Brown J 2003, Gould 1999, Malberg 2000, Santarelli 2003). Other factors, such as adrenal hormones, stress, age and drugs of abuse negatively influence neurogenesis (Cameron 1994, McEwen 1999, Kuhn 1996, Eisch 2004).

While the importance of neurogenesis cannot be overstated, the failure of axons to regenerate after spinal cord injury still remains one of the greatest challenges facing both medicine and neuroscience. An important development, however, has been the identification of inhibitory proteins in CNS myelin. One problem that causes the failure of CNS neuron regeneration is inhibition of neurite outgrowth by certain bioactive molecules. Myelin contributes to a number of proteins that have shown to inhibit neurite process outgrowth. NogoA is the first protein identified on the surface of the oligodendrocytes and some axons. Other proteins that can contribute to inhibition include myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp) and the proteoglycan versican.

It is believed that the central nervous system (CNS) environment could limit axonal regeneration after injury. Indeed, CNS myelin has been identified as a major factor contributing to regenerative failure. There are those in the field that believe, and have provided evidence, that CNS myelin contains proteins that inhibit axonal growth.

Various strategies have been proposed for overcoming myelin inhibition. One strategy that has been effective has been to elevate the levels of intracellular cAMP. Some manners in which this may be done include: a peripheral conditioning lesion, administration of cAMP analogues, priming with neurotrophins or treatment with the phosphodiesterase inhibitor rolipram (PDE4 inhibitor). The effects of cAMP may be transcription dependent, and cAMP-mediated activation of CREB may lead to upregulation and expression of genes such as arginase I and interleukin-6. The products of these genes are believed to promote axonal regeneration, which raises the possibility that other cAMP-regulated genes could yield additional agents that would be beneficial in the treatment of spinal cord injury. However, with regard to increasing the expression of IL-6, one significant disadvantage to this mechanism of action may be that IL-6 is a potentially harmful pro-inflammatory cytokine, meaning, it is possible that high levels of IL-6 could actually exacerbate the inflammation that occurs after spinal cord injury which could then lead to increase in cell death. Indeed, a factor supporting this concern is that IL-6 transgenic mice have been observed to have extensive astrogliosis, neurodegeneration, and breakdown of the blood brain barrier.

SUMMARY OF THE INVENTION

It is an advantage of the present invention that a PDE1 inhibitor (e.g., a compound of any of Formula I-XI) may act as a neuroprotective agent and/or neuroregenerative agent. In the event of a CNS injury (e.g., spinal cord injury), disease, or disorder, the compounds and methods disclosed herein may be employed to aid or enhance neurite outgrowth and axonal regeneration even in the presence of myelin inhibitors.

Without being bound by any particular theory, it is believed to be at least one advantage of the present invention that the administration of a PDE1 inhibitor (e.g., any compound of Formula I-XI) may act to increase levels of intracellular cAMP and initiate the transcription of genes that are necessary for overcoming myelin inhibitors and promoting neurite outgrowth and/or axonal regeneration in the case of a CNS disease, disorder, or injury.

Furthermore, it is believed to be an advantage that the administration of a PDE1 inhibitor (e.g., a compound of any of Formula I-XI) may elevate the intracellular levels of both cAMP as well as cGMP. Without being bound by theory, this rise in both cAMP and cGMP may serve as a counterbalance to the potentially detrimental effects that may be associated with chronically elevated levels of intracellular calcium. It has been observed that elevated levels of intracellular calcium could have some type of involvement in the development of various degenerative diseases. For instance, one possible explanation is that elevated levels of intracellular calcium (e.g., chronically elevated levels of intracellular calcium) could lead to the activation of PDE1 by calmodulin which would have a negative effect on the expression of cAMP.

However, without being bound by any theory, it is believed that one potential benefit of the administration of a PDE1 inhibitor (e.g., a compound of any of Formula IXI) is that this may lead to not only an increase in cAMP, but also cGMP. This increase in intracellular cGMP may lead to an increase in the activity of PKG, preventing a further rise in intracellular calcium levels. Thus, without being bound by any theory, the administration of a PDE1 inhibitor (e.g., a compound of any of Formula I-XI) could have the dual benefit of, for example, playing a beneficial role in axonal regeneration (and/or being neuroprotective) while simultaneously decreasing or lessening the degenerative effects that are possibly associated with elevated intracellular calcium levels.

In one embodiment the invention comprises compositions and methods to treat or prevent a CNS disease, disorder, or injury (e.g., spinal cord injury, e.g., spinal muscular atrophy, e.g., motor neuron injury), wherein the method comprises administration of an effective amount of a PDE1 inhibitor (e.g., a compound of any of Formula I-XI) to modulate intracellular levels of cAMP. In one embodiment, this increase in intracellular cAMP is neuroprotective and/or aids in the increase or stimulation of neurogenesis (e.g., the PDE1 inhibitor increases neurite outgrowth and/or axonal regeneration).

In still a further embodiment the invention comprises compositions and methods to treat or prevent injuries to the peripheral nervous system (PNS) wherein the method comprises administration of a PDE1 inhibitor to increase intracellular levels of cAMP which (either directly or indirectly) increases nerve regeneration and/or is protective against further nerve damage.

In one embodiment the invention comprises compositions and methods to prevent a CNS disease or disorder in a subject that is at risk for developing said disease or disorder, wherein the method comprises:

1.) Obtaining a sample from the subject;

2.) Measuring the levels of intracellular calcium from the sample;

3.) Comparing the levels of intracellular calcium in the biological sample to a reference standard;

4.) Determining whether a patient is at risk for developing a CNS disease or disorder based upon the level of intracellular calcium compared to the reference standard;

5.) Administering a PDE1 inhibitor (e.g., a compound of any of Formula I-XI) to a subject based upon the subject's levels of intracellular calcium (e.g., administration of a PDE1 inhibitor to a subject because they have elevated intracellular calcium levels compared to the reference standard).

DETAILED DESCRIPTION OF THE INVENTION

Compounds for Use in the Methods of the Invention

In one embodiment, the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are optionally substituted 4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or 4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, e.g., a Compound of Formula II, e.g., II-A or II-B:

wherein

-   -   (i) Q is C(═O), C(═S), C(═N(R₂₀)) or CH₂;     -   (ii) L is a single bond, —N(H)—, —CH₂—, —S—, —S(O)— or —S(O₂)—;     -   (iii) R₁ is H or C₁₋₄ alkyl (e.g., methyl);     -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂         and R₃ are, independently,         -   H         -   C₁₋₆alkyl (e.g., methyl, isopropyl) optionally substituted             with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂             is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),         -   aryl,         -   heteroaryl,         -   (optionally hetero)arylalkoxy,         -   (optionally hetero)arylC₁₋₆alkyl; or         -   R₂ and R₃ together form a 3- to 6-membered ring;         -   or         -   R₂ is H and R₃ and R₄ together form a di-, tri- or             tetramethylene bridge (pref. wherein the R₃ and R₄ together             have the cis configuration, e.g., where the carbons carrying             R₃ and R₄ have the R and S configurations, respectively);         -   or     -   (v) R₅ is         -   a) -D-E-F, wherein:             -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                 prop-2-yn-1-ylene);             -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                 arylene (e.g., phenylene) or heteroarylene (e.g.,                 pyridylene);             -   F is                 -   H,                 -   aryl (e.g., phenyl),                 -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                     example, pyrid-2-yl, imidazol-1-yl,                     1,2,4-triazol-1-yl),                 -   halo (e.g., F, Br, Cl),                 -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                 -   —C(O)—R₁₅,                 -   —N(R₁₆)(R₇), or                 -   C₃₋₇cycloalkyl optionally containing at least one                     atom selected from a group consisting of N or O                     (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,                     pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or                     morpholinyl);             -   wherein D, E and F are independently and optionally                 substituted with one or more halo (e.g., F, Cl or Br),                 C₁₋₄alkyl (e.g., methyl), haloC₁₋₄alkyl (e.g.,                 trifluoromethyl), C₁₋₄alkoxy (e.g., methoxy), hydroxy,                 C₁₋₄carboxy, or an additional aryl or heteroaryl (e.g.,                 biphenyl or pyridylphenyl),             -   for example, F is heteroaryl, e.g., pyridyl substituted                 with one or more halo (e.g., 6-fluoropyrid-2-yl,                 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                 4,6-dichloropyrid-2-yl), haloC₁₋₄alkyl (e.g.,                 5-trifluoromethylpyrid-2-yl) or C₁₋₄alkyl (e.g.,                 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl,                 substituted with one or more halo (e.g., 4-fluorophenyl)                 or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl)                 optionally substituted with a C₁₋₆alkyl (e.g.,                 1-methylpyrrolidin-3-yl); or         -   b) a substituted heteroarylalkyl, e.g., substituted with             haloC₁₋₄alkyl;         -   c) attached to the nitrogen on the pyrrolo portion of             Formula II-A or II-B and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                 R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                 or F), and R₁₀ is                 -   halogen,                 -   C₁₋₄alkyl,                 -   haloC₁₋₄alkyl (e.g., triflouromethyl)                 -   C₁₋₄alkoxy (e.g. methoxy),                 -   C₃₋₇cycloalkyl,                 -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                     piperidinyl),                 -   C₁₋₄haloalkyl (e.g., trifluoromethyl),                 -   aryl (e.g., phenyl),                 -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                     pyrid-4-yl), or thiadiazolyl (e.g.,                     1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,                     imidazol-1-yl), triazolyl (e.g.,                     1,2,4-triazol-1-yl), tetrazolyl,                 -   arylcarbonyl (e.g., benzoyl),                 -   alkylsulfonyl (e.g., methylsulfonyl),                 -   heteroarylcarbonyl, or                 -   alkoxycarbonyl;             -   wherein the aryl, heteroaryl, cycloalkyl or                 heterocycloalkyl is independently, optionally                 substituted with one or more C₁₋₄alkyl (e.g., methyl),                 halogen (e.g., chloro or fluoro), haloC₁₋₄alkyl (e.g.,                 trifluoromethyl), hydroxy, C₁₋₄carboxy, —SH or an                 additional aryl, heteroaryl (e.g., biphenyl or                 pyridylphenyl) or C₃₋₈cycloalkyl,             -   preferably R₁₀ is phenyl, pyridyl, piperidinyl or                 pyrrolidinyl optionally substituted with the                 substituents previously defined, e.g. optionally                 substituted with halo or alkyl             -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                 R₁₀, respectively, is not present;

    -   (vi) R₆ is         -   H,         -   C₁₋₄alkyl (e.g., methyl, ethyl, n-propyl, isobutyl),         -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),         -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl, piperidinyl,             morpholinyl),         -   aryl (e.g., phenyl),         -   heteroaryl (e.g., pyrid-4-yl),         -   arylC₁₋₄alkyl (e.g., benzyl),         -   arylamino (e.g., phenylamino),         -   heteroarylamino,         -   N,N-diC₁₋₄alkylamino,         -   N,N-diarylamino,         -   N-aryl-N-(arylC₁₋₄alkyl)amino (e.g.,             N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or         -   —N(R₁₈)(R₁₉),         -   wherein the aryl and heteroaryl are optionally substituted             with one or more C₁₋₄alkyl (e.g., methyl), halogen (e.g.,             chloro or fluoro), haloC₁₋₄alkyl (e.g., trifluoromethyl),             hydroxy, C₁₋₄carboxy, or an additional aryl, heteroaryl             (e.g., biphenyl or pyridylphenyl) or C₃₋₈ cycloalkyl;

    -   (vii) R₇ is H, C₁₋₆alkyl (e.g., methyl or ethyl), halogen (e.g.,         Cl), —N(R₁₈)(R₁₉), hydroxy or C₁₋₆alkoxy;

    -   (viii) n=0 or 1;

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,         independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally         hetero)arylC₁₋₄alkoxy, (optionally hetero)arylC₁₋₄alkyl or R₁₄         can form a bridge with R₂ or R₄;

    -   (x) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl (e.g.,         —OCH₃)

    -   (xi) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xii) R₁₈ and R₁₉ are independently         -   H,         -   C₁₋₄alky (e.g., methyl, ethyl, n-propyl, isobutyl),         -   C₃₋₈cycloalky (e.g., cyclohexyl or cyclopenyl),         -   heteroC₃₋₈cycloalky (e.g., pyrrolidinyl, piperidinyl,             morpholinyl),         -   aryl (e.g., phenyl) or         -   heteroaryl (e.g., pyridyl),         -   wherein said aryl and heteroaryl are optionally substituted             with one or more             -   halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),             -   hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or                 2-hydroxyphenyl),             -   C₁₋₄alkyl (e.g., methyl),             -   haloC₁₋₄alkyl (e.g., trifluoromethyl),             -   C₁₋₄carboxy, or             -   an additional aryl, heteroaryl (e.g., biphenyl or                 pyridylphenyl) or C₃₋₈cycloalkyl,

    -   (xiii) R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl;         in free or salt form.

In another embodiment, the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are Compound of Formula I, e.g. Formula I-A and I-B:

wherein

-   -   (i) Q is C(═O), C(═S), C(═N(R₂₀)) or CH₂;     -   (ii) L is a single bond, —N(H)—, —CH₂—, —S—, —S(O)— or —S(O₂)—;     -   (iii) R₁ is H or C₁₋₄ alkyl (e.g., methyl);     -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂         and R₃ are, independently,         -   H or C₁₋₆alkyl (e.g., methyl, isopropyl) optionally             substituted with halo or hydroxy (e.g., R₂ and R₃ are both             methyl, or R₂ is H and R₃ is methyl, ethyl, isopropyl or             hydroxyethyl),         -   aryl,         -   heteroaryl,         -   (optionally hetero)arylalkoxy, or         -   (optionally hetero)arylC₁₋₆alkyl;         -   or         -   R₂ is H and R₃ and R₄ together form a di-, tri- or             tetramethylene bridge (pref. wherein the R₃ and R₄ together             have the cis configuration, e.g., where the carbons carrying             R₃ and R₄ have the R and S configurations, respectively);     -   (v) R₅ is         -   a) -D-E-F, wherein:             -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                 prop-2-yn-1-ylene);             -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                 arylene (e.g., phenylene) or heteroarylene (e.g.,                 pyridylene);             -   F is                 -   H,                 -   aryl (e.g., phenyl),                 -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                     example, pyrid-2-yl, imidazol-1-yl,                     1,2,4-triazol-1-yl),                 -   halo (e.g., F, Br, Cl),                 -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                 -   —C(O)—R₁₅,                 -   —N(R₁₆)(R₁₇), or                 -   C₃₋₇cycloalkyl optionally containing at least one                     atom selected from a group consisting of N or O                     (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,                     pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or                     morpholinyl);             -   wherein D, E and F are independently and optionally                 substituted with one or more halo (e.g., F, Cl or Br),                 C₁₋₄alkyl (e.g., methyl), haloC₁₋₄alkyl (e.g.,                 trifluoromethyl), for example, F is heteroaryl, e.g.,                 pyridyl substituted with one or more halo (e.g.,                 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl,                 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,                 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),                 haloC₁₋₄alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or                 C₁₋₄alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl,                 e.g., phenyl, substituted with one or more halo (e.g.,                 4-fluorophenyl) or F is a C₃₋₇ heterocycloalkyl (e.g.,                 pyrrolidinyl) optionally substituted with a C₁₋₆alkyl                 (e.g., 1-methylpyrrolidin-3-yl); or         -   b) a substituted heteroarylalkyl, e.g., substituted with             haloalkyl;         -   c) attached to the nitrogen on the pyrrolo portion of             Formula I-A or I-B and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                 R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                 or F), and R₁₀ is                 -   halogen,                 -   C₁₋₄alkyl,                 -   C₃₋₇cycloalkyl,                 -   C₁₋₄haloalkyl (e.g., trifluoromethyl),                 -   aryl (e.g., phenyl),                 -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl),                     or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),                     diazolyl, triazolyl, tetrazolyl,                 -   arylcarbonyl (e.g., benzoyl),                 -   alkylsulfonyl (e.g., methylsulfonyl),                 -   heteroarylcarbonyl, or                 -   alkoxycarbonyl;             -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                 R₁₀, respectively, is not present;

    -   (vi) R₆ is         -   H,         -   C₁₋₄alkyl,         -   C₃₋₇cycloalkyl (e.g., cyclopentyl),         -   aryl (e.g., phenyl),         -   heteroaryl (e.g., pyrid-4-yl),         -   arylC₁₋₄alkyl (e.g., benzyl),         -   arylamino (e.g., phenylamino),         -   heteroarylamino,         -   N,N-diC₁₋₄alkylamino,         -   N,N-diarylamino,         -   N-aryl-N-(arylC₁₋₄alkyl)amino (e.g.,             N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or         -   —N(R₁₈)(R₁₉);         -   wherein the aryl or heteroaryl is optionally substituted             with one or more halo (e.g., F, Cl), hydroxy or C₁₋₆alkoxy;

    -   (vii) R₇ is H, C₁₋₆alkyl, halogen (e.g., Cl), —N(R₈)(R₁₉);

    -   (viii) n=0 or 1;

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,         independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally         hetero)arylC₁₋₄alkoxy or (optionally hetero)arylC₁₋₄alkyl;

    -   (x) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl (e.g.,         —OCH₃)

    -   (xi) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xii) R₁₈ and R₁₉ are independently H, C₁₋₄alky or aryl (e.g.,         phenyl) wherein said aryl is optionally substituted with one or         more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl) or hydroxy         (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl)

    -   (xiii) R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl; in free or salt         form.

The invention further provides optionally substituted 4,5,7,8-tetrahydro-(optionally 4-thioxo or 4-imino)-(1H or 2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or 4,5,7,8,9-pentahydro-(1H or 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, in free or salt form, e.g., (1 or 2 and/or 3 and/or 5)-substituted 4,5,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine, 4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine, 4,5,7,8-tetrahydro-(1H or 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine, 7,8-dihydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione or 7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione compounds, e.g., a Compound of Formula III:

wherein

-   -   (xiv) Q is C(═S), C(═N(R₂₀)) or CH₂;     -   (xv) L is a single bond, —N(H)—, —CH₂—;     -   (xvi) R₁ is H or C₁₋₄ alkyl (e.g., methyl or ethyl);     -   (xvii) R₄ is H or C₁₋₆ alkyl (e.g., methyl, isopropyl) and R₂         and R₃ are, independently:         -   H or C₁₋₆alkyl (e.g., methyl or isopropyl) optionally             substituted with halo or hydroxy (e.g., R₂ and R₃ are both             methyl, or R₂ is H and R₃ is methyl, ethyl, isopropyl or             hydroxyethyl),         -   aryl,         -   heteroaryl,         -   (optionally hetero)arylalkoxy,         -   (optionally hetero)arylC₁₋₆alkyl, or         -   R₂ and R₃ together form a 3- to 6-membered ring;         -   or         -   R₂ is H and R₃ and R₄ together form a di-, tri- or             tetramethylene bridge (pref. wherein the R₃ and R₄ together             have the cis configuration, e.g., where the carbons carrying             R₃ and R₄ have the R and S configurations, respectively);     -   (xviii) R₅ is         -   d) -D-E-F, wherein:             -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                 prop-2-yn-1-ylene);             -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                 arylene (e.g., phenylene) or heteroarylene (e.g.,                 pyridylene);             -   F is                 -   H,                 -   aryl (e.g., phenyl),                 -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                     example, pyrid-2-yl, imidazol-1-yl,                     1,2,4-triazol-1-yl),                 -   halo (e.g., F, Br, Cl),                 -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                 -   —C(O)—R₁₅,                 -   —N(R₁₆)(R₁₇),                 -   —S(O)₂R₂₁ or                 -   C₃₋₇cycloalkyl optionally containing at least one                     atom selected from a group consisting of N or O                     (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,                     pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or                     morpholinyl);             -   wherein D, E and F are independently and optionally                 substituted with one or more:                 -   halo (e.g., F, Cl or Br),                 -   C₁₋₄alkyl (e.g., methyl),                 -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                 -   C₁₋₄alkoxy) or                 -   C₁₋₄alkyl (e.g., 5-methylpyrid-2-yl),             -   for example, F is heteroaryl, e.g., pyridyl substituted                 with one or more halo (e.g., 6-fluoropyrid-2-yl,                 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                 4,6-dichloropyrid-2-yl),             -   or F is aryl, e.g., phenyl, substituted with one or more                 halo (e.g., 4-fluorophenyl)             -   or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl)                 optionally substituted with a C₁₋₆alkyl (e.g.,                 1-methylpyrrolidin-3-yl);             -   or         -   e) a substituted heteroarylalkyl, e.g., substituted with             haloalkyl;         -   f) attached to one of the nitrogens on the pyrazolo portion             of Formula III and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                 R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                 or F), and R₁₀ is:                 -   halogen,                 -   C₁₋₄alkyl,                 -   C₃₋₇cycloalkyl,                 -   hetC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                     piperidinyl),                 -   C₁₋₄haloalkyl (e.g., trifluoromethyl),                 -   aryl (e.g., phenyl),                 -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl),                     or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),                     diazolyl, triazolyl, tetrazolyl,                 -   arylcarbonyl (e.g., benzoyl),                 -   alkylsulfonyl (e.g., methylsulfonyl),                 -   heteroarylcarbonyl, or                 -   alkoxycarbonyl;             -   wherein the aryl, heteroaryl, cycloalkyl or                 heterocycloalkyl is independently and optionally                 substituted with one or more halo (e.g., F or Cl),                 C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl (e.g.,                 trifluoromethyl), —SH;             -   preferably R₁₀ is phenyl, pyridyl, piperidinyl or                 pyrrolidinyl optionally substituted with the                 substituents previously defined, e.g. optionally                 substituted with halo or alkyl             -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                 R₁₀, respectively, is not present;

    -   (xix) R₆ is         -   H,         -   C₁₋₄alkyl,         -   C₃₋₇cycloalkyl (e.g., cyclopentyl),         -   aryl (e.g., phenyl),         -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),         -   arylC₁₋₄alkyl (e.g., benzyl),         -   arylamino (e.g., phenylamino),         -   heterarylamino,         -   N,N-diC₁₋₄alkylamino,         -   N,N-diarylamino,         -   N-aryl-N-(arylC₁₋₄alkyl)amino (e.g.,             N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or         -   —N(R₁₈)(R₁₉);         -   wherein the aryl or heteroaryl is optionally substituted             with one or more halo (e.g., F, Cl), hydroxy, C₁₋₆alkyl,             C₁₋₆alkoxy, C₃₋₈ cycloalkyl, for example, R₆ is             4-hydroxyphenyl or 4-fluorophenyl,

    -   (xx) n=0 or 1;

    -   (xxi) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,         independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally         hetero)arylC₁₋₄alkoxy, (optionally hetero)arylC₁₋₄alkyl or R₁₃         or R₁₄ can form a bridge with R₂ or R₄;

    -   (xxii) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl         (e.g., —OCH₃)

    -   (xxiii) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xxiv) R₁₈ and R₁₉ are independently         -   H,         -   C₁₋₄alky,         -   C₃₋₈cycloalkyl,         -   heteroC₃₋₈cycloalkyl,         -   aryl (e.g., phenyl), or         -   heteroaryl,         -   wherein said aryl or heteroaryl is optionally substituted             with one or more             -   halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),             -   hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or                 2-hydroxyphenyl),             -   C₁₋₆alkyl,             -   haloC₁₋₆alkyl,             -   C₁₋₆alkoxy,             -   aryl,             -   heteroaryl, or             -   C₃₋₈cycloalkyl;

    -   (xxv) R₂₀ is H, C₁₋₄alkyl (e.g., methyl) or C₃₋₇cycloalkyl,

    -   (xxvi) R₂₁ is C₁₋₆alkyl; in free or salt form.

In yet another embodiment, the invention also provides a Compound of Formula IV:

wherein

-   -   (i) Q is C(═S), C(═N(R₂₀)) or CH₂;     -   (ii) L is a single bond, —N(H)—, —CH₂—;     -   (iii) R₁ is H or C₁₋₄ alkyl (e.g., methyl or ethyl);     -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl, isopropyl) and R₂ and         R₃ are, independently, H or C₁₋₆alkyl (e.g., methyl or         isopropyl) optionally substituted with halo or hydroxy (e.g., R₂         and R₃ are both methyl, or R₂ is H and R₃ is methyl, ethyl,         isopropyl or hydroxyethyl), aryl, heteroaryl, (optionally         hetero)arylalkoxy, or (optionally hetero)arylC₁₋₆alkyl;         -   or         -   R₂ is H and R₃ and R₄ together form a di-, tri- or             tetramethylene bridge (pref. wherein the R₃ and R₄ together             have the cis configuration, e.g., where the carbons carrying             R₃ and R₄ have the R and S configurations, respectively);     -   (v) R₅ is         -   a) -D-E-F, wherein:             -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                 prop-2-yn-1-ylene);             -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                 arylene (e.g., phenylene) or heteroarylene (e.g.,                 pyridylene);             -   F is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl,                 diazolyl, triazolyl, for example, pyrid-2-yl,                 imidazol-1-yl, 1,2,4-triazol-1-yl), halo (e.g., F, Br,                 Cl), haloC₁₋₄alkyl (e.g., trifluoromethyl), —C(O)—R₁₅,                 —N(R₁₆)(R₁₇), —S(O)₂R₂₁ or C₃₋₇ cycloalkyl optionally                 containing at least one atom selected from a group                 consisting of N or O (e.g., cyclopentyl, cyclohexyl,                 pyrrolidinyl (e.g., pyrrolidin-3-yl),                 tetrahydro-2H-pyran-4-yl, or morpholinyl);             -   wherein D, E and F are independently and optionally                 substituted with one or more:                 -   halo (e.g., F, Cl or Br),                 -   C₁₋₄alkyl (e.g., methyl),             -   haloC₁₋₄alkyl (e.g., trifluoromethyl),             -   for example, F is heteroaryl, e.g., pyridyl substituted                 with one or more halo (e.g., 6-fluoropyrid-2-yl,                 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                 4,6-dichloropyrid-2-yl), haloC₁₋₄alkyl (e.g.,                 5-trifluoromethylpyrid-2-yl) or C₁₋₄alkyl (e.g.,                 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl,                 substituted with one or more halo (e.g., 4-fluorophenyl)             -   or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl)                 optionally substituted with a C₁₋₆alkyl (e.g.,                 1-methylpyrrolidin-3-yl);             -   or         -   b) a substituted heteroarylalkyl, e.g., substituted with             haloalkyl;         -   c) attached to one of the nitrogens on the pyrazolo portion             of Formula IV and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                 R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                 or F), and R₁₀ is:                 -   halogen,                 -   C₁₋₄alkyl,                 -   C₃₋₇cycloalkyl,                 -   C₁₋₄haloalkyl (e.g., trifluoromethyl),                 -   aryl (e.g., phenyl),                 -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl),                     or                 -   thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),                     diazolyl, triazolyl, tetrazolyl,                 -   arylcarbonyl (e.g., benzoyl),                 -   alkylsulfonyl (e.g., methylsulfonyl),                 -   heteroarylcarbonyl, or                 -   alkoxycarbonyl;             -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                 R₁₀, respectively, is not present;

    -   (vi) R₆ is         -   H,         -   C₁₋₄alkyl,         -   C₃₋₇cycloalkyl (e.g., cyclopentyl),         -   aryl (e.g., phenyl),         -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),         -   arylC₁₋₄alkyl (e.g., benzyl),         -   arylamino (e.g., phenylamino),         -   heterarylamino,         -   N,N-diC₁₋₄alkylamino,         -   N,N-diarylamino,         -   N-aryl-N-(arylC₁₋₄alkyl)amino (e.g.,             N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or         -   —N(R₁₈)(R₁₉);         -   wherein the aryl or heteroaryl is optionally substituted             with one or more halo (e.g., F, Cl), hydroxy or C₁₋₆alkoxy,             for example, R₆ is 4-hydroxyphenyl or 4-fluorophenyl,

    -   (vii) n=0 or 1;

    -   (viii) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,         independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally         hetero)arylC₁₋₄alkoxy or (optionally hetero)arylC₁₋₄alkyl;

    -   (ix) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl (e.g.,         —OCH₃)

    -   (x) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xi) R₁₈ and R₁₉ are independently H, C₁₋₄alky or aryl (e.g.,         phenyl) wherein said aryl is optionally substituted with one or         more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl) or hydroxy         (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl)

    -   (xii) R₂₀ is H, C₁₋₄alkyl (e.g., methyl) or C₃₋₇cycloalkyl,

    -   (xiii) R₂₁ is C₁₋₆alkyl; in free or salt form.

In still yet another embodiment, the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis which are described herein are selected from any of the Applicant's own publications and applications: US 2008-0188492 A1, US 2010-0173878 A1, US 2010-0273754 A1, US 2010-0273753 A1, WO 2010/065153, WO 2010/065151, WO 2010/065151, WO 2010/065149, WO 2010/065147, WO 2010/065152, WO 2011/153129, WO 2011/133224, WO 2011/153135, WO 2011/153136, WO 2011/153138, U.S. Ser. No. 12/064,599, U.S. Ser. No. 12/514,712, U.S. Ser. No. 12/517,945, U.S. Ser. No. 13/203,365, U.S. Ser. No. 13/319,807, U.S. Ser. No. 13/500,941 and U.S. Ser. No. 14/209,258, the entire contents of each of which are incorporated herein by reference in their entireties.

In yet another embodiment the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula V:

wherein

-   -   (i) R₁ is H or C₁₋₄ alkyl (e.g., methyl);     -   (ii) R₄ is H or C₁₋₄ alkyl and R₂ and R₃ are, independently, H         or C₁₋₄ alkyl (e.g., R₂ and R₃ are both methyl, or R₂ is H and         R₃ is isopropyl), aryl, heteroaryl, (optionally         hetero)arylalkoxy, or (optionally hetero)arylalkyl;     -   or     -   R₂ is H and R₃ and R₄ together form a di-, tri- or         tetramethylene bridge (pref. wherein the R₃ and R₄ together have         the cis configuration, e.g., where the carbons carrying R₃ and         R₄ have the R and S configurations, respectively);     -   (iii) R₅ is a substituted heteroarylalkyl, e.g., substituted         with haloalkyl     -   or     -   R₅ is attached to one of the nitrogens on the pyrazolo portion         of Formula V and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F), and R₁₀ is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is not present; and (iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heterarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylakyl)amino (e.g., N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino); and (v) n=0 or 1; (vi) when n=1, A is —C(R₁₃R₁₄)—

-   -   wherein R₁₃ and R₁₄, are, independently, H or C₁₋₄ alkyl, aryl,         heteroaryl, (optionally hetero)arylalkoxy or (optionally         hetero)arylalkyl;         in free, salt or prodrug form, including its enantiomers,         diastereoisomers and racemates.

In one embodiment the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula VI:

wherein:

-   -   (i) R₁ is H or alkyl;     -   (ii) R₂ is H, alkyl, cycloalkyl, haloalkyl, alkylaminoalkyl,         hydroxyalkyl, arylalkyl, heteroarylalkyl, or alkoxyarylalkyl;     -   (iii) R₃ is heteroarylmethyl or formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂ are independently H or halogen; and R₁₀ is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, alkyl sulfonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, or aminocarbonyl;

-   -   (iv) R₄ is aryl or heteroaryl; and     -   (v) R₅ is H, alkyl, cycloalkyl, heteroaryl, aryl, p-benzylaryl;         provided that when X, Y or X is nitrogen, R₈, R₉ or R₁₀,         respectively, is not present; wherein “alk” or “alkyl” refers to         C₁₋₆ alkyl and “cycloalkyl” refers to C₃₋₆ cycloalkyl, in free,         salt or physiologically hydrolysable and acceptable ester         prodrug form.

In one embodiment the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula VII:

(i) X is C₁₋₆alkylene (e.g., methylene, ethylene or prop-2-yn-1-ylene); (ii) Y is a single bond, alkynylene (e.g., —C≡C—), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene); (iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloC₁₋₆alkyl (e.g., trifluoromethyl), —C(O)—R¹, —N(R²)(R³), or C₃₋₇cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl); (iv) R¹ is C₁₋₆alkyl, haloC₁₋₆alkyl, —OH or —OC₁₋₆alkyl (e.g., —OCH₃); (v) R² and R³ are independently H or C₁₋₆alkyl; (vi) R⁴ and R⁵ are independently H, C₁₋₆alky or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) or C₁₋₆alkoxy; (vii) wherein X, Y and Z are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), C₁₋₆alkyl (e.g., methyl), haloC₁₋₆alkyl (e.g., trifluoromethyl), for example, Z is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC₁₋₆alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C₁₋₆-alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl), in free, salt or prodrug form.

In one embodiment the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula VIII:

wherein

-   -   (i) R₁ is H or C₁₋₆alkyl;     -   (ii) R₂ is         -   H,         -   C₁₋₆alkyl,         -   C₃₋₈cycloalkyl optionally substituted with one or more             amino,         -   C₃₋₈heterocycloalkyl optionally substituted with C₁₋₆alkyl,         -   C₃₋₈cycloalkyl-C₁₋₆-alkyl,         -   C₁₋₆haloalkyl,         -   C₀₋₆alkylaminoC₀₋₆alkyl,         -   hydroxyC₁₋₆alkyl,         -   arylC₀₋₆alkyl,         -   heteroarylalkyl,         -   C₁₋₆alkoxyarylC₁₋₆alkyl, or         -   -G-J wherein:             -   G is a single bond or, alkylene;             -   J is cycloalkyl or heterocycloalkyl optionally                 substituted with alkyl;     -   (iii) R₃ is         -   a) -D-E-F wherein             -   1. D is single bond, C₁₋₆alkylene or arylC₁₋₆alkylene;             -   2. E is a C₁₋₆alkylene, arylene, C₁₋₆alkylarylene,                 aminoC₁₋₆ alkylene- or amino; and             -   3. F is heteroC₃₋₈cycloalkyl optionally substituted with                 C₁₋₆ alkyl;     -   (iv) R₄ is aryl optionally substituted with one or more halo,         hydroxyl or C₁₋₆ alkoxy; heteroaryl; or heteroC₃₋₆cycloalkyl;         and     -   (v) R₅ is H, C₁₋₆alkyl, C₃₋₈cycloalkyl, heteroaryl, aryl or         p-benzylaryl;         wherein “alk”, “alkyl”, “haloalkyl” or “alkoxy” refers to C₁₋₆         alkyl and “cycloalkyl” refers to C₃₋₈cycloalkyl;         in free or salt form.

In one embodiment the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula IX:

wherein

-   -   (i) Q is —C(═S)—, —C(═N(R₆))— or —C(R₁₄)(R₁₅)—;     -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);     -   (iii) R₂ is         -   H,         -   C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or             2,2-dimethylpropyl) wherein said alkyl group is optionally             substituted with one or more halo (e.g., fluoro) or hydroxy             (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or             3-hydroxy-2-methylpropyl),         -   haloC₁₋₆alkyl (e.g., trifluoromethyl or             2,2,2-trifluoroethyl),         -   N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g., 2-(dimethylamino)ethyl or             2-aminopropyl),         -   arylC₀₋₆alkyl (e.g., phenyl or benzyl), wherein said aryl is             optionally substituted with one or more C₁₋₆alkoxy, for             example, C₁₋₆alkoxyarylC₀₋₆alkyl (e.g., 4-methoxybenzyl),         -   heteroarylC₀₋₆alkyl (e.g., pyridinylmethyl), wherein said             heteroaryl is optionally substituted with one or more             C₁₋₆alkoxy (e.g., C₁₋₆ alkoxyheteroarylC₁₋₆alkyl);         -   -G-J wherein G is a single bond or C₁₋₆alkylene (e.g.,             methylene) and J is C₃₋₈cycloalkyl or heteroC₃₋₈cycloalkyl             (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl)             wherein the cycloalkyl and heterocycloalkyl group are             optionally substituted with one or more C₁₋₆alkyl or amino,             for example,             -   —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., —C₀₋₄alkyl-cyclopentyl,                 —C₀₋₄ alkyl-cyclohexyl or —C₀₋₄alkyl-cyclopropyl),                 wherein said cycloalkyl is optionally substituted with                 one or more C₁₋₆alkyl or amino (for example,                 2-aminocyclopentyl or 2-aminocyclohexyl),             -   —C₀₋₄alkyl-C₃₋₈heterocycloalkyl (e.g.,                 —C₀₋₄alkyl-pyrrolidinyl, for example,                 —C₀₋₄alkylpyrrolidin-3-yl) wherein said heterocycloalkyl                 is optionally substituted with C₁₋₆alkyl (e.g., methyl),                 for example, 1-methylpyrrolidin-3-yl,                 1-methyl-pyrrolindin-2-yl,                 1-methyl-pyrrolindin-2-yl-methyl or                 1-methyl-pyrrolindin-3-yl-methyl);     -   (iv) R₃ is         -   1) -D-E-F wherein:             -   D is a single bond, C₁₋₆alkylene (e.g., methylene), or                 arylC₁₋₆ alkylene (e.g., benzylene or —CH₂C₆H₄—);             -   E is                 -   a single bond,                 -   C₁₋₄alkylene (e.g., methylene, ethynylene,                     prop-2-yn-1-ylene),                 -   C₀₋₄alkylarylene (e.g., phenylene or —C₆H₄—,                     -benzylene- or —CH₂C₆H₄—), wherein the arylene group                     is optionally substituted with halo (e.g., Cl or F),                 -   heteroarylene (e.g., pyridinylene or                     pyrimidinylene),                 -   aminoC₁₋₆alkylene (e.g., —CH₂N(H)—),                 -   amino (e.g., —N(H)—);                 -   C₃₋₈cycloalkylene optionally containing one or more                     heteroatom selected from N or O (e.g.,                     piperidinylene),             -   F is                 -   H,                 -   halo (e.g., F, Br, Cl),                 -   C₁₋₆alkyl (e.g., isopropyl or isobutyl),                 -   haloC₁₋₆alkyl (e.g., trifluoromethyl),                 -   aryl (e.g., phenyl),                 -   C₃₋₈cycloalkyl optionally containing one or more                     atom selected from a group consisting of N, S or O                     (e.g., cyclopentyl, cyclohexyl, piperidinyl,                     pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or                     morpholinyl), and optionally substituted with one or                     more C₁₋₆alkyl (e.g., methyl or isopropyl), for                     example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl,                     pyrrolidin-2-yl, piperidin-2-yl,                     1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl,                 -   heteroaryl (e.g., pyridyl (for example, pyrid-2-yl),                     pyrimidinyl (for example, pyrimidin-2-yl),                     thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl),                     diazolyl (e.g., pyrazolyl (for example,                     pyrazol-1-yl) or imidazolyl (for example,                     imidazol-1-yl, 4-methylimidazolyl,                     1-methylimidazol-2-yl)), triazolyl (e.g.,                     1,2,4-triazol-1-yl), tetrazolyl (e.g.,                     tetrazol-5-yl), alkyloxadiazolyl (e.g.,                     5-methyl-1,2,4-oxadiazol), wherein said heteroaryl                     is optionally substituted with one or more                     C₁₋₆alkyl, halo (e.g., fluoro) or haloC₁₋₆ alkyl;                 -   C₁₋₆alkoxy,                 -   —O-haloC₁₋₆alkyl (e.g., —O—CF₃),                 -   C₁₋₆alkylsulfonyl (for example, methylsulfonyl or                     —S(O)₂CH₃),                 -   —C(O)—R₁₃, wherein R₁₃ is —N(R₁₄)(R₁₅), C₁₋₆alkyl                     (e.g., methyl), —OC₁₋₆alkyl (e.g., —OCH₃),                     haloC₁₋₆alkyl (trifluoromethyl), aryl (e.g.,                     phenyl), or heteroaryl;                 -   —N(R₁₄)(R₁₅);             -   or         -   2) a substituted heteroarylC₁₋₆aklyl, e.g., substituted with             haloC₁₋₆ alkyl;             -   or         -   3) attached to one of the nitrogens on the pyrazolo portion             of Formula I and is a moiety of Formula A

-   -   -   -   wherein:                 -   X, Y and Z are, independently, N or C,                 -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                     (e.g., Cl or F); and                 -   R₁₀ is                 -    halogen (e.g., fluoro or chloro),                 -    C₁₋₆alkyl,                 -    C₃₋₈cycloalkyl,                 -    heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl or                     piperidinyl),                 -    haloC₁₋₆alkyl (e.g., trifluoromethyl),                 -    aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl,                     (for example, pyrid-2-yl) or e.g., thiadiazolyl (for                     example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl                     (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,                     tetrazol-5-yl), alkyloxadiazolyl (e.g.,                     5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,                     pyrazol-1-yl),                 -    wherein said aryl, heteroaryl, cycloalkyl or                     heterocycloalkyl is optionally substituted with one                     or more C₁₋₆alkyl (e.g., methyl), halogen (e.g.,                     chloro or fluoro), haloC₁₋₆alkyl (e.g.,                     trifluoromethyl), hydroxy, carboxy, —SH, or an                     additional aryl or heteroaryl (e.g., biphenyl or                     pyridylphenyl),                 -    C₁₋₆alkyl sulfonyl (e.g., methyl sulfonyl),                 -    arylcarbonyl (e.g., benzoyl),                 -    heteroarylcarbonyl,                 -    C₁₋₆alkoxycarbonyl, (e.g., methoxycarbonyl),                 -    Aminocarbonyl,                 -    —N(R₁₄)(R₁₅);                 -    preferably R₁₀ is phenyl, pyridyl, piperidinyl or                     pyrrolidinyl optionally substituted with the                     substituents previously defined, e.g. optionally                     substituted with halo or alkyl;                 -   provided that when X, Y or X is nitrogen, R₈, R₉ or                     R₁₀, respectively, is not present;

    -   (v) R₄ and R₅ are independently:         -   H,         -   C₁₋₆alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl),         -   C₃₋₈cycloalkyl (e.g., cyclopentyl or cyclohexyl),         -   C₃₋₈heterocycloalkyl (e.g., pyrrolidinyl (for example             pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for             example, piperidin-1-yl), morpholinyl),         -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or         -   —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or             pyrazol-3-yl)         -   wherein said aryl or heteroaryl is optionally substituted             with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g.,             4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or another aryl             group (e.g., biphenyl-4-ylmethyl);

    -   (vi) R₆ is H, C₁₋₆alkyl (e.g., methyl or ethyl) or         C₃₋₈cycloalkyl;

    -   (vii) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl, in free or         salt form.

In one embodiment the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are Formula X, e.g.:

Formula X-A Formula X-B wherein

-   -   (i) Q is —C(═S)—, —C(═O)—, —C(═N(R₇))— or —C(R₁₄)(R₁₅)—;     -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);     -   (iii) R₂ is H, C₁₋₆alkyl (e.g., isopropyl, isobutyl,         2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is         optionally substituted with halo (e.g., fluoro) or hydroxy         (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), for         example, R₂ may be a trifluoromethyl or 2,2,2-trifluoroethyl,         N(R₁₄)(R₁₅)— C₁₋₆alkyl (e.g., 2-(dimethylamino)ethyl or         2-aminopropyl), arylC₁₋₆alkyl (e.g., phenyl or benzyl),         heteroaryl C₁₋₆alkyl (e.g., pyridinylmethyl),         C₁₋₆alkoxyaryl-C₁₋₆alkyl (e.g., 4-methoxybenzyl); -G-J wherein:         -   G is a single bond or, alkylene (e.g., methylene); J is             cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl,             pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with             one or more C₁₋₆alkyl (e.g., (1-methylpyrolidin-2-yl)),             amino (e.g., —NH₂), for example, -G-J may be             —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., cyclopentyl, cyclohexyl or             cyclopropylmethyl) optionally substituted with one or more             C₁₋₆ alkyl, amino (e.g., —NH₂), for example,             2-aminocyclopentyl or 2-aminocyclohexyl, wherein said             cycloalkyl optionally contains one or more heteroatom             selected from N and O (e.g., pyrrolidinyl, for example,             pyrrolidin-3-yl or pyrrolidin-2-yl,             1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl,             l-methyl-pyrrolindin-2-yl-methyl or             1-methyl-pyrrolindin-3-yl-methyl);

(iv) R₃ is

-   -   1) -D-E-F wherein:     -   D is a single bond, Ci₋₆alkylene (e.g., methylene), or         arylalkylene     -   (e.g., p-benzylene or —CH₂C₆H₄—);     -   E is a single bond,     -   C₁₋₆alkylene (e.g., methylene) C₂₋₆alkynylene (e.g., ethynylene,         prop-2-yn-1-ylene), ethynylene, prop-2-yn-1-ylene),         —Co₋₄alkylarylene (e.g., phenylene or —C₆H₄—, -benzyle{acute         over (η)}ε- or —CH₂C₆H₄—), wherein the arylene group is         optionally substituted with halo (e.g., Cl or F), heteroarylene         (e.g., pyridinylene or pyrimidinylene), aminoC₁₋₆alkylene (e.g.,         —CH₂N(H)—), amino (e.g., —N(H)—);         -   C₃₋₈cycloalkylene optionally containing one or more             heteroatom selected from N or O (e.g., piperidinylene),         -   F is         -   H,         -   halo (e.g., F, Br, Cl), C₁₋₆alkyl (e.g., isopropyl or             isobutyl), haloC₁₋₆alkyl         -   (e.g., trifluoromethyl),         -   aryl (e.g., phenyl),         -   C₃₋₈cycloalkyl optionally containing at least one atom             selected from a group consisting of N or O (e.g.,             cyclopentyl, N cyclohexyl, piperidinyl, pyrrolidinyl,             tetrahydro-2H-pyran-4-yl, or morpholinyl), said cycloalkyl             is optionally substituted with C₁₋₆alkyl (e.g., methyl or             isopropyl), for example, l-methylpyrrolidin-2-yl,             pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl,             l-methyrpiperidin-2-yl, 1-ethylpiperidin-2-yl, heteroaryl             optionally substituted with C₁₋₆alkyl, (e.g., pyridyl, (for             example, pyrid-2-yl), pyrimidinyl (for example,             pyrimidin-2-yl), thiadiazolyl (for example,             1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for             example, pyrazol-1-yl) or imidazolyl (for example,             imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl),             triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,             tetrazol-5-yl), alkoxadiazolyl (e.g.,             5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl),             wherein said         -   heteroaryl is optionally substituted with halo (e.g.,             fluoro) or haloCi₋₆alkyl, for example, 6-fluoropyrid-2-yl;             amino (e.g., —NH₂), C₁₋₆alkoxy, —O-haloC₁₋₆alkyl (e.g.,             —O—CF₃), C₁₋₆alkylsulfonyl (for example, methylsulfonyl or             —S(O)₂CH₃),         -   —C(O)—R₁₃,         -   —N(R₁₄)(R₁₅); or     -   2) a substituted heteroarylaklyl, e.g., substituted with         haloalkyl; or     -   3) attached to the nitrogen on the pyrrolo portion of Formula I         and is a moiety of Formula A

-   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁         and R₁₂ are independently H or halogen (e.g., Cl or F); and R₁₀         is halogen, C₁₋₆alkyl,     -   C₁₋₆alkoxy (e.g., methoxy), C₃₋₈cycloalkyl, heteroC₃₋₈cycloalkyl         (e.g., pyrrolidinyl) haloC₁₋₆alkyl (e.g., trifluoromethyl), aryl         (e.g., phenyl), heteroaryl (e.g., pyridyl, (for example,         pyrid-2-yl) or e.g., thiadiazolyl (for example,         1,2,3-thiadiazol-4-yl), diazolyl (e.g., imidazolyl or         pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl         (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g.,         5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl),         C₁₋₆alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g.,         benzoyl), heteroarylcarbonyl,     -   alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; wherein         the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is         optionally substituted with one or more C₁₋₆alkyl (e.g.,         methyl), halogen (e.g., chloro or fluoro), haloC₁₋₆alkyl (e.g.,         trifluoromethyl), hydroxy, carboxy, —SH, or an additional aryl         or heteroaryl (e.g., biphenyl or pyridylphenyl) preferably R₁₀         is phenyl or pyridyl, e.g., 2-pyridyl optionally substituted         with the substituents previously defined;     -   provided that when X, Y or X is nitrogen, R₈, R₉ or R₁₀,         respectively, is not present; (v) R₄ and R₅ are independently H,         Ci₋₆alkyl (e.g., methyl, isopropyl),     -   C₃₋₈cycloalkyl (e.g., cyclopentyl), C₃₋₈heterocycloalkyl (e.g.,         pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g.,         pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or         heteroaryl is optionally substituted with halo (e.g.,         4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl,         C₁₋₆alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);     -   (vi) R₆ is H, C₁₋₆alkyl (e.g., methyl), hydroxy, Ci₋₆alkoxy,         aryloxy, —N(R₁₆)(R₁₇), oxo (e.g., =0), or C₃₋₈Cycloalkyl;     -   (vii) R₇ is H, C₁₋₆alkyl (e.g., methyl) or C₃₋₈cycloalkyl         wherein said cycloalkyl is optionally substituted with one or         more oxo (e.g., 2,5-dioxopyrrolidin-1-yl);     -   (viii) R₁₃ is —N(R₁₄)(R₁₅), C₁₋₆alkyl (e.g., methyl),         —OC₁₋₆alkyl (e.g., —OCH₃), haloC₁₋₆alkyl (trifluoromethyl), aryl         (e.g., phenyl), or heteroaryl; and     -   (ix) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl;     -   (x) R₁₋₆ and R₁₇ are independently H, C₁₋₆alkyl, aryl (e.g.,         phenyl), heteroaryl, wherein said aryl or heteroaryl is         optionally substituted with halo (e.g., fluoro), C₁₋₆alkoxy         (e.g., methoxy); in free or salt form.

In one embodiment the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are Formula XI:

wherein

-   -   (i) L is S, SO or SO₂;     -   (ii) R₂ is H or C₁₋₆alkyl (e.g., methyl or ethyl);     -   (iii) R₂ is     -   H,     -   C₁₋₆alkyl (e.g., isopropyl, isobutyl, neopentyl, 2-methylbutyl,         2,2-dimethylpropyl) wherein said alkyl group is optionally         substituted with halo (e.g., fluoro) or hydroxy (e.g.,         1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), —C₀₋₄alkyl-C₃₋₈         cycloalkyl (e.g., cyclopentyl, cyclohexyl) optionally         substituted with one or more amino (e.g., —NH₂), for example,         2-aminocyclopentyl or 2-aminocyclohexyl), wherein said         cycloalkyl optionally contains one or more heteroatom selected         from N and O and is optionally substituted with C₁₋₆alkyl (e.g.,         1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl,         1-methyl-pyrrolindin-2-yl-methyl or         1-methyl-pyrrolindin-3-yl-methyl), C₃₋₈heterocycloalkyl (e.g.,         pyrrolidinyl, for example, pyrrolidin-3-yl) optionally         substituted with C₁₋₆alkyl (e.g., methyl), for example,         l-methylpyrrolidin-3-yl, C₃₋₈ cycloalkyl-C₁₋₆alkyl (e.g.,         cyclopropylmethyl), haloC₁₋₆alkyl (e.g., trifluoromethyl,         2,2,2-trifluoroethyl), —N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g.,         2-(dimethylamino)ethyl, 2-aminopropyl), hydroxyC₁₋₆alkyl (e.g.,         (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl),         arylC₀₋₆alkyl (e.g., benzyl), heteroarylC₁₋₆alkyl (e.g.,         pyridinylmethyl), C₁₋₆alkoxyarylC₁₋₆alkyl (e.g.,         4-methoxybenzyl); -G-J wherein: G is a single bond or, alkylene         (e.g., methylene);     -   J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl,         pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with         C₁₋₆alkyl (e.g., (1-methylpyrolidin-2-yl));     -   (iv) R₃ is attached to one of the nitrogens on the pyrazolo         portion of Formula I and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F); and R₁₀ is halogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl or piperidinyl) haloC₁₋₆alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-15 yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-i-yi), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; preferably phenyl, pyridyl, e.g., 2-pyridyl, piperidinyl, or pyrrolidinyl; wherein the aryl, heteroaryl cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo (e.g., F or Cl), C₁₋₆alkly, C₁₋₆alkoxy, C₁₋₄ haloalkyl (e.g., trifluoromethyl), and/or —SH, provided that when X, Y or X is nitrogen, R₈, R₉ or R₁₀, respectively, is not present; (v) R₄ is H, C₁₋₆alkyl (e.g., methyl, isopropyl), C₃₋₈cycloalkyl (e.g., cyclopentyl), C₃₋₈heterocycloalkyl (e.g., pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl); (vi) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl, in free or salt form.

The invention further provides the use of PDE1 inhibitors of any of the preceding formulae (e.g., Formula I, II, III, IV, V, VI, VII, VIII, LX, X, XI), wherein the compound is selected from any of the following:

The invention further provides the use of PDE1 inhibitors of any of the preceding formulae (e.g., Formula I, II, IH, IV, V, VI, VII, VIII, IX, X, XI), wherein the compound is selected from any of the following:

In yet another embodiment, the invention further provides the use of PDE1 inhibitors of any of the preceding formulae (e.g., Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI), wherein the compound is selected from any of the following:

In yet another embodiment, the invention further provides the use of PDE1 inhibitors of any of the preceding formulae (e.g., Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI), wherein the compound is selected from any of the following:

In a still further embodiment, the selective PDE1 inhibitors are selected from the following compounds which can be used either alone or in combination with another PDE inhibitor (e.g., any of Formula I-XI):

In one embodiment, selective PDE1 inhibitors of the any of the preceding formulae (e.g., Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI) are compounds that inhibit phosphodiesterase-mediated (e.g., PDE1-mediated, especially PDE1A or PDE1C-mediated) hydrolysis of cGMP, e.g., the preferred compounds have an IC₅₀ of less than 1 μM, preferably less than 500 nM, preferably less than 50 nM, and preferably less than 5 nM in an immobilized-metal affinity particle reagent PDE assay, in free or salt form.

If not otherwise specified or clear from context, the following terms herein have the following meanings:

-   -   (a) “Alkyl” as used herein is a saturated or unsaturated         hydrocarbon moiety, preferably saturated, preferably having one         to six carbon atoms, which may be linear or branched, and may be         optionally mono-, di- or tri-substituted, e.g., with halogen         (e.g., chloro or fluoro), hydroxy, or carboxy.     -   (b) “Cycloalkyl” as used herein is a saturated or unsaturated         nonaromatic

hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, and which may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. Wherein the cycloalkyl optionally contains one or more atoms selected from N and O and/or S, said cycloalkyl may also be a heterocycloalkyl.

-   -   (c) “Heterocycloalkyl” is, unless otherwise indicated, saturated         or unsaturated nonaromatic hydrocarbon moiety, preferably         saturated, preferably comprising three to nine carbon atoms, at         least some of which form a nonaromatic mono- or bicyclic, or         bridged cyclic structure, wherein at least one carbon atom is         replaced with N, O or S, which heterocycloalkyl may be         optionally substituted, e.g., with halogen (e.g., chloro or         fluoro), hydroxy, or carboxy.     -   (d) “Aryl” as used herein is a mono or bicyclic aromatic         hydrocarbon,

preferably phenyl, optionally substituted, e.g., with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl).

-   -   (e) “Heteroaryl” as used herein is an aromatic moiety wherein         one or more of the atoms making up the aromatic ring is sulfur         or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl,         which may be optionally substituted, e.g., with alkyl, halogen,         haloalkyl, hydroxy or carboxy.     -   (f) For ease of reference, the atoms on the pyrazolo-pyrimidine         core of the Compounds of the Invention are numbered in         accordance with the numbering depicted in Formula I, unless         otherwise noted.     -   (g) Wherein E is phenylene, the numbering is as follows:

-   -   (h) It is intended that wherein the substituents end in “ene”,         for example, alkylene, phenylene or arylalkylene, said         substitutents are intended to bridge or be connected to two         other substituents. Therefore, methylene is intended to be —CH₂—         and phenylene intended to be —C₆H₄— and arylalkylene is intended         to be —C₆H₄—CH₂— or —CH₂—C₆H₄—.     -   (i) The Compounds of the Invention are intended to be numbered         as follows:

Compounds of the Invention, e.g., substituted 4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or 4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, e.g., Compounds of Formula I (Formula I-A and I-B), or a Compound of Formula II (e.g., II-A or II-B), may exist in free or salt form, e.g., as acid addition salts. In this specification unless otherwise indicated, language such as “Compounds of the Invention” is to be understood as embracing the compounds in any form, for example free or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form. The Compounds of the Invention are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention or their pharmaceutically acceptable salts, are therefore also included.

Compounds of the Invention, encompassing any of the compounds disclosed herein, e.g., optionally substituted 4,5,7,8-tetrahydro-(optionally 4-thioxo or 4-imino)-(1H or 2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or 4,5,7,8,9-pentahydro-(1H or 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, e.g., (1 or 2 and/or 3 and/or 5)-substituted 4,5,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine, 4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine, 4,5,7,8-tetrahydro-(1H or 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine, 7,8-dihydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione or 7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione compounds, e.g., Compounds of Formula III, or Compound of Formula IV as described herein, may exist in free or salt form, e.g., as acid addition salts.

Compounds of the Invention may in some cases also exist in prodrug form. A prodrug form is compound which converts in the body to a Compound of the Invention. For example when the Compounds of the Invention contain hydroxy or carboxy substituents, these substituents may form physiologically hydrolysable and acceptable esters. As used herein, “physiologically hydrolysable and acceptable ester” means esters of Compounds of the Invention which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Invention which have hydroxy substituents) or alcohols (in the case of Compounds of the Invention which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered. Therefore, wherein the Compound of the Invention contains a hydroxy group, for example, Compound-OH, the acyl ester prodrug of such compound, i.e., Compound-O—C(O)—C₁₋₄ alkyl, can hydrolyze in the body to form physiologically hydrolysable alcohol (Compound-OH) on the one hand and acid on the other (e.g., HOC(O)—C₁₋₄alkyl). Alternatively, wherein the Compound of the Invention contains a carboxylic acid, for example, Compound-C(O)OH, the acid ester prodrug of such compound, Compound-C(O)O—C₁₋₄alkyl can hydrolyze to form Compound-C(O)OH and HO—C₁₋₄alkyl. As will be appreciated the term thus embraces conventional pharmaceutical prodrug forms.

In another embodiment, the invention further provides a pharmaceutical composition comprising a Compound of the Invention, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable carrier.

Compounds of the Invention may in some cases also exist in prodrug form. A prodrug form is compound which converts in the body to a Compound of the Invention. For example when the Compounds of the Invention contain hydroxy or carboxy substituents, these substituents may form physiologically hydrolysable and acceptable esters. As used herein, “physiologically hydrolysable and acceptable ester” means esters of Compounds of the Invention which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Invention which have hydroxy substituents) or alcohols (in the case of Compounds of the Invention which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered. Therefore, wherein the Compound of the Invention contains a hydroxy group, for example, Compound-OH, the acyl ester prodrug of such compound, i.e., Compound-O—C(O)—C₁₋₄ alkyl, can hydrolyze in the body to form physiologically hydrolysable alcohol (Compound-OH) on the one hand and acid on the other (e.g., HOC(O)—C₁₋₄alkyl). Alternatively, wherein the Compound of the Invention contains a carboxylic acid, for example, Compound-C(O)OH, the acid ester prodrug of such compound, Compound-C(O)O—C₁₋₄alkyl can hydrolyze to form Compound-C(O)OH and HO—C₁₋₄alkyl. As will be appreciated the term thus embraces conventional pharmaceutical prodrug forms.

In another embodiment, the invention further provides a pharmaceutical composition comprising a Compound of the Invention, in free, pharmaceutically acceptable salt or prodrug form, in admixture with a pharmaceutically acceptable carrier.

Methods of Making Compounds of the Invention

The compounds of the Invention and their pharmaceutically acceptable salts may be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. Such methods include, but not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.

Various starting materials and/or Compounds of the Invention may be prepared using methods described in US 2008-0188492 A1, US 2010-0173878 A1, US 2010-0273754 A1, US 2010-0273753 A1, WO 2010/065153, WO 2010/065151, WO 2010/065151, WO 2010/065149, WO 2010/065147, WO 2010/065152, WO 2011/153129, WO 2011/133224, WO 2011/153135, WO 2011/153136, WO 2011/153138. All references cited herein are hereby incorporated by reference in their entirety.

The Compounds of the Invention include their enantiomers, diastereoisomers and racemates, as well as their polymorphs, hydrates, solvates and complexes. Some individual compounds within the scope of this invention may contain double bonds. Representations of double bonds in this invention are meant to include both the E and the Z isomer of the double bond. In addition, some compounds within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any of the optically pure stereoisomers as well as any combination of stereoisomers.

It is also intended that the Compounds of the Invention encompass their stable and unstable isotopes. Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non-isotopic analogs. For example, the hydrogen atom at a certain position on the Compounds of the Invention may be replaced with deuterium (a stable isotope which is non-raradioactive). Examples of known stable isotopes include, but not limited to, deuterium, ¹³C, ¹⁵N, ¹⁸O. Alternatively, unstable isotopes, which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., ¹²³I ¹³¹I, ¹²⁵I, ¹¹C, ¹⁸F, may replace the corresponding abundant species of I, C and F. Another example of useful isotope of the compound of the invention is the ¹¹C isotope. These radio isotopes are useful for radio-imaging and/or pharmacokinetic studies of the compounds of the invention.

Melting points are uncorrected and (dec) indicates decomposition. Temperature are given in degrees Celsius (° C.); unless otherwise stated, operations are carried out at room or ambient temperature, that is, at a temperature in the range of 18-25° C. Chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) is carried out on silica gel plates. NMR data is in the delta values of major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Conventional abbreviations for signal shape are used. Coupling constants (J) are given in Hz. For mass spectra (MS), the lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks Solvent mixture compositions are given as volume percentages or volume ratios. In cases where the NMR spectra are complex, only diagnostic signals are reported.

TERMS AND ABBREVIATIONS

-   -   BuLi=n-butyllithium     -   Bu^(t)OH=tert-butyl alcohol,     -   CAN=ammonium cerium (IV) nitrate,     -   DIPEA=diisopropylethylamine,     -   DMF=N,N-dimethylforamide,     -   DMSO=dimethyl sulfoxide,     -   Et₂O=diethyl ether,     -   EtOAc=ethyl acetate,     -   equiv.=equivalent(s),     -   h=hour(s),     -   HPLC=high performance liquid chromatography,     -   LDA=lithium diisopropylamide     -   MeOH=methanol,     -   NBS=N-bromosuccinimide     -   NCS=N-chlorosuccinimide     -   NaHCO₃=sodium bicarbonate,     -   NH₄OH=ammonium hydroxide,     -   Pd₂(dba)₃=tris[dibenzylideneacetone]dipalladium(0)     -   PMB=p-methoxybenzyl,     -   POCl₃=phosphorous oxychloride,     -   SOCl₂=thionyl chloride,     -   TFA=trifluoroacetic acid,     -   TFMSA=trifluoromethanesulfonic acid     -   THF=tetrahedrofuran.         Methods of Using Compounds of the Invention

In one embodiment the invention provides Method I, wherein Method I further comprises the prophylaxis and/or treatment of diseases, disorders, and injuries of the central nervous system, wherein the method comprises the administration of an effective amount of a PDE1 inhibitor (e.g., any compound of Formula I-XI) to modulate the level of intracellular cAMP.

For example, Method I also includes:

-   1.1. Method I, wherein the administration of the PDE1 inhibitor     enhances the axonal growth or regeneration, and/or slows or reverses     the loss of such cells in a neurodegenerative condition. -   1.2. Any of preceding Method-I, et seq., wherein the CNS disease,     disorder, or injury, refers to damage that directly or indirectly     affects the normal functioning of the CNS. -   1.3. Any of preceding Method-I, et seq., wherein the CNS disease,     disorder, or injury can be a structural, physical, or mechanical     impairment and may be caused by physical impact e.g.: crushing,     compression, or stretching of nerve fibers. -   1.4. Any of preceding Method-I, et seq., wherein the CNS disease,     disorder, or injury is a spinal cord injury. -   1.5. Method of 1.4, wherein the PDE1 inhibitor slows or arrests the     progression of the spinal cord injury. -   1.6. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor     slows or arrests axonal filament degradation. -   1.7. Any of preceding Method-I, et seq. wherein the CNS disease,     disorder, or injury relates to motor neuron trauma.     1.8. Any of preceding Method-I, et seq., wherein the disease,     disorder, or injury is selected from the group consisting of:     neurological traumas and injuries, surgery related trauma and/or     injury, retinal injury and trauma, injury related to epilepsy, cord     injury, spinal cord injury, brain injury, brain surgery, trauma     related brain injury, trauma related to spinal cord injury, brain     injury related to cancer treatment, spinal cord injury related to     cancer treatment, brain injury related to infection, brain injury     related to inflammation, spinal cord injury related to infection,     spinal cord injury related to inflammation, brain injury related to     environmental toxin, and spinal cord injury related to environmental     toxin. -   1.9. Any of preceding Method-I, et seq., wherein the CNS disease,     disorder, or injury includes neuron or nerve fibers that may be     destroyed by or degraded by an illness (e.g., Parkinson's Disease),     a chemical imbalance, or a physiological malfunction such as anoxia     (e.g., stroke), aneurysm, or reperfusion. -   1.10. Any of preceding Method-I, et seq., wherein the CNS disease,     disorder, or injury is a neurodegenerative disorder. -   1.11. Method of 1.10, wherein the neurodegenerative disease,     disorder, or injury is selected from the group consisting of:     Alzheimer's disease, Multiple Sclerosis, Spinal Muscular Atrophy,     Glaucoma, Frontotemporal dementia, Dementia with Lewy bodies,     Corticobasal degeneration, Progressive supranuclear palsy, Prion     disorders, Huntington's disease, Multiple system atrophy,     Parkinson's disease, Amyotrophic lateral sclerosis, Hereditary     spastic paraparesis, Spinocerebellar atrophies, Friedreich's ataxia,     Amyloidoses, Metabolic (diabetes) related disorders, Toxin related     disorders, chronic CNS inflammation, Charcot Marie Tooth disease,     diabetic neuropathy, cancer chemotherapy (e.g., by vinca alkaloids     and doxorubicin), brain damage associated with stroke and ischemia     associated with stroke, and neurological disorders including, but     not limited to, various peripheral neuropathic and neurological     disorders related to neurodegeneration including, but not limited     to: trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy,     myasthenia gravis, muscular dystrophy, amyotrophic lateral     sclerosis, progressive muscular atrophy, progressive bulbar     inherited muscular atrophy, herniated, ruptured or prolapsed     vertebral disk syndromes, cervical spondylosis, plexus disorders,     thoracic outlet destruction syndromes, peripheral neuropathies such     as those caused by e.g., lead, acrylamides, gamma-diketones, carbon     disulfide, dapsone, ticks, porphyria, and Gullain-Barre syndrome. -   1.12. Any of preceding Method-I, et seq., wherein the CNS disease,     disorder, or injury is a CNS lesion, a seizure (e.g.,     electroconvulsive seizure treatment; epileptic seizures), radiation,     chemotherapy and/or stroke or other ischemic injury. -   1.13. Any of preceding Method-I, et seq., wherein the administration     of the PDE1 inhibitor is used to replenish, replace, and/or     supplement neurons and/or glial cells. -   1.14. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor     (e.g., a compound of any of Formula I-XI) is administered to a     subject or a patient in need thereof. -   1.15. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor     (e.g., a compound of any of Formula I-XI) elevates the level or     expression of intracellular cAMP. -   1.16. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor     (e.g., a compound of any of Formula I-XI) decreases the level or     expression of intracellular cAMP. -   1.17. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor     (e.g., a compound of any of Formula I-XI) modulates activity of PKA     or PKG. -   1.18. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor     (e.g., a compound of any of Formula I-XI) increases the activity of     PKA or PKG. -   1.19. Any of preceding Method-I, et seq., wherein the administration     of the PDE1 inhibitor (e.g., a compound of any of Formula I-XI)     increases the level of both cAMP and cGMP. -   1.20. Any of preceding Method-I, et seq., wherein the administration     of the PDE1 inhibitor (e.g., a compound of any of Formula I-XI)     elevates the level of intracellular cAMP, and wherein this increased     level intracellular cAMP has neuroprotective and/or     neuroregenerative properties.     1.21. Any of preceding Method-I, et seq., comprising administration     of an effective amount of the PDE1 inhibitor (e.g., a compound of     any of Formula I-XI) to a patient that suffers from a disease or     disorder related to elevated (e.g., chronically elevated)     intracellular calcium levels, and wherein the PDE1 inhibitor     prevents a further rise in said calcium levels. -   1.22. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor     is administered either alone or in combination with another active     agent. -   1.23. Any of preceding Method-I, et seq., wherein the disease,     disorder, or injury is related to motor neurons, and wherein the     motor neuron disease, disorder, or injury is Multiple Sclerosis. -   1.24. Any of preceding Method-II, et seq., wherein the PDE1     inhibitor is administered in combination with another active agent     in order to treat Multiple Sclerosis. -   1.25. The method of 2.11, wherein the active agent is selected from     the group consisting of: Interferon, Glatiramer acetate,     Natalizumab, Gilenya® (fingolimod), Fampyra®, immunosuppresents, and     corticoids.

In another embodiment the invention provides for Method II, wherein Method II comprises compositions and methods of treatment or prophylaxis of a peripheral nervous system (PNS) disease, disorder, or injury, wherein the method comprises administration of an effective amount of a PDE1 inhibitor to increase intracellular levels of cAMP.

For example, Method II also includes:

-   2.1. Method II, wherein the PNS disease, disorder, or injury, refers     to damage that directly or indirectly affects the normal functioning     of the CNS. -   2.2. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor     is administered to a subject or a patient in need thereof. -   2.3. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor     elevates the level or expression of intracellular cAMP. -   2.4. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor     (e.g., directly or indirectly) modulates activity of PKA and/or PKG. -   2.5. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor     (e.g., directly or indirectly) increases the activity of PKA and/or     PKG. -   2.6. Any of preceding Method-II, et seq., wherein the administration     of the PDE1 inhibitor increases the level of cAMP and/or cGMP. -   2.7. Any of preceding Method-II, et seq., wherein the administration     of the PDE1 inhibitor elevates the level of intracellular cAMP, and     wherein this increased level intracellular cAMP levels protects     nerve fibers, regenerates nerve fibers, or promotes nerve fiber     growth (e.g., axonal regeneration). -   2.8. Any of preceding Method-II, et seq., comprising administration     of an effective amount of the PDE1 inhibitor (e.g., a compound of     any of Formula I-XI) to a patient that suffers from a disease or     disorder related to elevated (e.g., chronically elevated)     intracellular calcium levels. -   2.9. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor     is administered either alone or in combination with another active     agent. -   2.10. The method of 2.9, wherein the active agent is selected from     the IGF (e.g., IGF-1) or a steroid. -   2.11. Any of preceding Method-II, et seq. wherein the PNS disease,     disorder, or injury is selected from the group consisting of:     neuropathy (e.g., peripheral neuropathy, autonomic neuropathy, and     mononeuropathy), sciatica, carpal tunnel syndrome, polyneuropathy,     diabetic neuropathy, postherpetic neuralgia, and thoracic outlet     syndrome.

In another embodiment the invention provides for Method III, wherein Method III comprises compositions and methods to prevent a CNS disease or disorder in a subject that is at risk for developing said disease or disorder, wherein the method comprises:

-   -   1.) Obtaining a sample from the subject;     -   2.) Measuring the levels of intracellular calcium from the         sample;     -   3.) Comparing the levels of intracellular calcium in the         biological sample to a reference standard;     -   4.) Determining whether a patient is at risk for developing a         CNS disease or disorder based upon the level of intracellular         calcium compared to the reference standard;     -   5.) Administering a PDE1 inhibitor (e.g., a compound of any of         Formula I-XI) to a subject based upon the subject's levels of         intracellular calcium (e.g., administration of a PDE1 inhibitor         to a subject because they have elevated intracellular calcium         levels compared to the reference standard).

For example, Method III also includes:

-   3.1. Method III, wherein the sample is a biological sample. -   3.2. Any of preceding Method-III, et seq., wherein the patient's     intracellular calcium levels are measured using a chemical     fluorescent probe. -   3.3. Any of preceding Method-III, et seq., wherein the patient's     intracellular calcium levels are elevated compared to a control     (e.g., reference standard). -   3.4. Any of preceding Method-III, et seq., wherein a PDE1 inhibitor     is administered to a patient that is shown to have elevated     intracellular calcium levels compared to a control (e.g., reference     standard). -   3.5. Any of preceding Method-III, et seq., wherein the     administration of a PDE1 inhibitor slows or prevents the development     of a CNS and/or PNS disease or disorder, wherein the CNS disease or     disorder is one that correlates to elevated (e.g., chronically     elevated) levels of intracellular calcium. -   3.6. Any of preceding Method-III, et seq., wherein the     administration of a PDE1 inhibitor decreases the likelihood that an     individual will develop a CNS and/or PNS disease or disorder,     wherein the CNS and/or PNS disease or disorder is one that     correlates with elevated (e.g., chronically elevated) levels of     intracellular calcium (e.g., any of the diseases, disorders or     injuries listed in Method I, et seq., and Method II, et seq.). -   3.7. Any of preceding Method-III, et seq., wherein the method     optionally comprises measuring the patient's intracellular levels of     cAMP or cGMP. -   3.8. Any of preceding Method-III, et seq., wherein the PDE1     inhibitor is administered either alone or in combination with     another active agent. -   3.9. Any of preceding Method-III, et seq., wherein the PDE1     inhibitor is administered because a patient has low levels of cAMP     and/or cGMP compared to a control subject.

The phrase “Compounds of the Invention” or “PDE1 inhibitors of the Invention” encompasses any and all of the compounds disclosed herewith, e.g., a Compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI, and any sub-formula (e.g., Formula II should be read as including both “Formula IIa and Formula IIb).

The words “treatment” and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease.

For methods of treatment, the word “therapeutically effective amount” as used herein refers to an amount of a drug (e.g., PDE1 inhibitor) sufficient to treat or ameliorate the pathological effects a CNS or PNS disease, disorder, or injury. For example, a therapeutically effective amount of a PDE1 inhibitor may be an amount sufficient to, e.g., increase intracellular levels of cAMP or cGMP, decrease intracellular levels of calcium, and/or increase neuroregeneration. Where relevant, a therapeutically effective amount may also be the amount of a PDE1 inhibitor necessary to slow or prevent the development of CNS or PNS disease or disorder.

The term “patient” or “subject” refers to human or non-human (i.e., animal) patient. In particular embodiment, the invention encompasses both human and nonhuman. In another embodiment, the invention encompasses nonhuman. In other embodiment, the term encompasses human.

The term “control subject” as used herein, refers to any human or nonhuman organism that does not have and/or is not suspected of having a disorder, syndrome, disease, condition and/or symptom. The term “reference standard” as used herein, refers to prior measurement and obtaining of results in a control population.

The term “biological sample” as used herein, may include any sample comprising biological material obtained from, e.g., an organism, body fluid, waste product, cell or part of a cell thereof, cell line, biopsy, tissue culture or other source containing a intracellular calcium, cAMP, or cGMP levels.

A “neurogenic agent” is defined as a chemical agent or reagent that can promote, stimulate, or otherwise increase the amount or degree or nature of neurogenesis in vivo or ex vivo or in vitro relative to the amount, degree, or nature of neurogenesis in the absence of the agent or reagent.

A “CNS injury” as used herein may include, e.g., damage to retinal ganglion cells, a traumatic brain injury, a stroke-related injury, a cerebral aneurism-related injury, a spinal cord injury or trauma, including monoplegia, diplegia, paraplegia, hemiplegia and quadriplegia, a neuroproliferative disorder, or neuropathic pain syndrome

A “PNS injury” as used herein may include, e.g., damage to the spinal or cranial nerves, wherein that damage may include a lesion or some acute or chronic trauma.

Compounds of the Invention, (e.g., any of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI) as hereinbefore described, in free or pharmaceutically acceptable salt form, may be used as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents.

Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular Compound of the Invention used, the mode of administration, and the therapy desired. Compounds of the Invention may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, e.g. for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. In larger mammals, for example humans, an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 150 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 or 150 mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of the Invention, together with a pharmaceutically acceptable diluent or carrier therefor.

Pharmaceutical compositions comprising Compounds of the Invention may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets, capsules, solutions, suspensions and the like.

EXAMPLES Example 1 Measurement of PDEIB Inhibition In Vitro Using IMAP Phosphodiesterase Assay Kit

Phosphodiesterase I B (PDEIB) is a calcium/calmodulin dependent phosphodiesterase enzyme that converts cyclic guanosine monophosphate (cGMP) to 5′-guanosine monophosphate (5′-GMP). PDEIB can also convert a modified cGMP substrate, such as the fluorescent molecule cGMP-fluorescein, to the corresponding GMP-fluorescein. The generation of GMP-fluorescein from cGMP-fluorescein can be quantitated, using, for example, the IMAP (Molecular Devices, Sunnyvale, Calif.) immobilized-metal affinity particle reagent.

Briefly, the IMAP reagent binds with high affinity to the free 5′-phosphate that is found in GMP-fluorescein and not in cGMP-fluorescein. The resulting GMPfluorescein-IMAP complex is large relative to cGMP-5 fluorescein. Small fluorophores that are bound up in a large, slowly tumbling, complex can be distinguished from unbound fluorophores, because the photons emitted as they fluoresce retain the same polarity as the photons used to excite the fluorescence.

In the phosphodiesterase assay, cGMP-fluorescein, which cannot be bound to IMAP, and therefore retains little fluorescence polarization, is converted to GMPfluorescein, which, when bound to IMAP, yields a large increase in fluorescence polarization (Amp). Inhibition of phosphodiesterase, therefore, is detected as a decrease in Amp. Enzyme assay

Materials: All chemicals are available from Sigma-Aldrich (St. Louis, Mo.) except for IMAP reagents (reaction buffer, binding buffer, FL-GMP and IMAP beads), which are available from Molecular Devices (Sunnyvale, Calif.).

Assay: The following phosphodiesterase enzymes may be used: 3′,5′-cyclic-nucleotide specific bovine brain phosphodiesterase (Sigma, St. Louis, Mo.) (predominantly PDEIB) and recombinant full length human PDE1A and PDE1B (r-hPDE1 A and r-hPDE1B respectively) which may be produced e.g., in HEK or SF9 cells by one skilled in the art. The PDE1 enzyme is reconstituted with 50% glycerol to 2.5 U/ml. One unit of enzyme will hydrolyze 1.0 μm of 3′,5′-cAMP to 5′-AMP per min at pH 7.5 at 30° C. One part enzyme is added to 1999 parts reaction buffer (30 μM CaCl 2, 10 U/ml of calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10 mM MgCl 2, 0.1% BSA, 0.05% NaN 3) to yield a final concentration of 1.25 mU/ml. 99 μM of diluted enzyme solution is added into each well in a flat bottom 96-well polystyrene plate to which 1 μM of test compound dissolved in 100% DMSO is added. The compounds are mixed and pre-incubated with the enzyme for 10 min at room temperature.

The FL-GMP conversion reaction is initiated by combining 4 parts enzyme and inhibitor mix with 1 part substrate solution (0.225 μM) in a 384-well microtiter plate. The reaction is incubated in dark at room temperature for 15 min. The reaction is halted by addition of 60 μM of binding reagent (1:400 dilution of IMAP beads in binding buffer supplemented with 1:1800 dilution of antifoam) to each well of the 384-well plate. The plate is incubated at room temperature for 1 hour to allow IMAP binding to proceed to completion, and then placed in an Envision multimode microplate reader (PerkinElmer, Shelton, Conn.) to measure the fluorescence polarization (Amp).

A decrease in GMP concentration, measured as decreased Amp, is indicative of inhibition of PDE activity. IC50 values are determined by measuring enzyme activity in the presence of 8 to 16 concentrations of compound ranging from 0.0037 nM to 80,000 nM and then plotting drug concentration versus AmP, which allows IC50 values to be estimated using nonlinear regression software (XLFit; IDBS, Cambridge, Mass.).

Example 2

A selective PDE1 inhibitor of the present invention demonstrates microsomal stability in human microsomal stability assays. The aforementioned selective PDE1 inhibitor demonstrates a K value less than 0.005, and demonstrates a half-life of T½ of about 275 minutes.

Example 3

A selective PDE1 inhibitor of the present invention demonstrates the ability to cross the blood-brain barrier. Following an injection of 10 mg/Kg in a suitable mouse model, the aforementioned selective PDE1 inhibitor is detectable at about 3 μM less than about 0.5 hours following the injection. 

The invention claimed is:
 1. A method for the treatment of a CNS injury, wherein the method comprises the administration of an effective amount of a PDE1 inhibitor to a subject in need thereof, wherein the administration of the PDE1 inhibitor modulates the subject's level of intracellular cAMP and is sufficient for axonal regeneration; and wherein the PDE1 inhibitor is a Compound of Formula IV:

wherein (i) Q is C(═S), C(═N(R₂₀)) or CH₂; (ii) L is a single bond, —N(H)—, —CH₂—; (iii) R₁ is H or C₁₋₄ alkyl; (iv) R₄ is H or C₁₋₆ alkyl and R₂ and R₃ are, independently, H or C₁₋₆alkyl optionally substituted with halo or hydroxy, aryl, heteroaryl, arylalkoxy, or arylC₁₋₆alkyl; or R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylene bridge; (v) R₅ is a) -D-E-F, wherein: D is C₁₋₄alkylene; E is a single bond, C₂₋₄alkynylene, arylene or heteroarylene; F is H, aryl, heteroaryl, halo, haloC₁₋₄alkyl, —C(O)—R₁₅, —N(R₁₆)(R₁₇), —S(O)₂R₂₁ or C₃₋₇cycloalkyl optionally containing at least one atom selected from a group consisting of N or O, tetrahydro-2H-pyran-4-yl, or morpholinyl; wherein D, E and F are independently and optionally substituted with one or more:  halo,  C₁₋₄alkyl, haloC₁₋₄alkyl, for example, F is heteroaryl, e.g., pyridyl substituted with one or more halo, haloC₁₋₄alkyl or C₁₋₄alkyl, or F is aryl, e.g., phenyl, substituted with one or more halo  or F is a C₃₋₇heterocycloalkyl optionally substituted with a C₁₋₆alkyl;  or b) a substituted heteroarylalkyl; c) attached to one of the nitrogens on the pyrazolo portion of Formula IV and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂ are independently H or halogen, and R₁₀ is:  halogen,  C₁₋₄alkyl,  C₃₋₇cycloalkyl,  C₁₋₄haloalkyl,  aryl,  heteroaryl, or  thiadiazolyl,  arylcarbonyl,  alkylsulfonyl,  heteroarylcarbonyl, or  alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is not present; (vi) R₆ is H, C₁₋₄alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, arylC₁₋₄alkyl, arylamino, heterarylamino, N,N-diC₁₋₄alkylamino, N,N-diarylamino, N-aryl-N-(arylC₁₋₄alkyl)amino, or —N(R₁₈)(R₁₉); wherein the aryl or heteroaryl is optionally substituted with one or more halo, hydroxy or C₁₋₆alkoxy, (vii) n=0; (viii) when n=1, A is —(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are, independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally hetero)arylC₁₋₄alkoxy or (optionally hetero)arylC₁₋₄alkyl; (ix) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl, (x) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl; (xi) R₁₈ and R₁₉ are independently H, C₁₋₄alky or aryl wherein said aryl is optionally substituted with one or more halo or hydroxy, (xii) R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl, (xiii) R₂₁ is C₁₋₆alkyl; in free or salt form.
 2. A method for the treatment of a CNS injury, wherein the method comprises the administration of an effective amount of a PDE1 inhibitor to a subject in need thereof, wherein the administration of the PDE1 inhibitor modulates the subject's level of intracellular cAMP and is sufficient for axonal regeneration, wherein the PDE1 inhibitor is a compound of Formula V:

wherein (i) R₁ is H or C₁₋₄ alkyl; (ii) R₄ is H or C₁₋₄ alkyl and R₂ and R₃ are, independently, H or C₁₋₄ alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl; or R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylene bridge; (iii) R₅ is a substituted heteroarylalkyl, or R₅ is attached to one of the nitrogens on the pyrazolo portion of Formula V and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂ are independently H or halogen, and R₁₀ is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or thiadiazolyl, diazolyl, triazolyl, tetrazolyl, arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is not present; and (iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heterarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylakyl)amino; and (v) n=0; (vi); wherein aryl is optionally substituted with C₁₋₄ alkyl, halogen, haloC₁₋₄alkyl, hydroxyl or C₁₋₄carboxy or an additional aryl or heteroaryl; or heteroaryl or thiadiazolyl is optionally substituted with C₁₋₄alkyl, halogen, haloC₁₋₄alkyl, hydroxyl or C₁₋₄carboxy; in free or pharmaceutically acceptable salt form.
 3. A method of claim 1, wherein the PDE1 inhibitor is compound of Formula VII:

(i) X is C₁₋₆alkylene; (ii) Y is a single bond, alkynylene, arylene or heteroarylene; (iii) Z is H, aryl, heteroaryl, halo, haloC₁₋₆alkyl, —C(O)—R¹, —N(R²)(R³), or C₃₋₇cycloalkyl optionally containing at least one atom selected from a group consisting of N or O; (iv) R¹ is C₁₋₆alkyl, haloC₁₋₆alkyl, —OH or —OC₁₋₆alkyl; (v) R² and R³ are independently H or C₁₋₆alkyl; (vi) R⁴ and R⁵ are independently H, C₁₋₆alky or aryl optionally substituted with one or more halo, hydroxy or C₁₋₆alkoxy; (vii) wherein X, Y and Z are independently and optionally substituted with one or more halo, C₁₋₆alkyl, haloC₁₋₆alkyl, for example, Z is heteroaryl, haloC₁₋₆alkyl or C₁₋₆-alkyl, or Z is aryl, substituted with one or more halo, in free, or salt form.
 4. The method according to claim 1, wherein the CNS injury is a spinal cord injury.
 5. The method according to claim 1, wherein the CNS injury relates to motor neuron trauma.
 6. The method according to claim 1, wherein the CNS injury is selected from the group consisting of: neurological traumas and injuries, surgery related trauma and/or injury, retinal injury and trauma, injury related to epilepsy, cord injury, spinal cord injury, brain injury, brain surgery, trauma related brain injury, trauma related to spinal cord injury, brain injury related to cancer treatment, spinal cord injury related to cancer treatment, brain injury related to infection, brain injury related to inflammation, spinal cord injury related to infection, spinal cord injury related to inflammation, brain injury related to environmental toxin, and spinal cord injury related to environmental toxin.
 7. A method of treatment of a PNS injury, wherein the method comprises administration of an effective amount of a PDE1 inhibitor to a subject in need thereof, in order to increase the subject's intracellular levels of cAMP, wherein the PDE1 inhibitor is a Compound of Formula IV:

wherein (xiv) Q is C(═S), C(═N(R₂₀)) or CH₂; (xv) L is a single bond, —N(H)—, —CH₂—; (xvi) R₁ is H or C₁₋₄ alkyl; (xvii) R₄ is H or C₁₋₆ alkyl and R₂ and R₃ are, independently, H or C₁₋₆alkyl optionally substituted with halo or hydroxy, aryl, heteroaryl, arylalkoxy, or arylC₁₋₆alkyl; or R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylene bridge; (xviii) R₅ is d) -D-E-F, wherein: D is C₁₋₄alkylene; E is a single bond, C₂₋₄alkynylene, arylene or heteroarylene; F is H, aryl, heteroaryl, halo, haloC₁₋₄alkyl, —C(O)—R₁₅, —N(R₁₆)(R₁₇), —S(O)₂R₂₁ or C₃₋₇cycloalkyl optionally containing at least one atom selected from a group consisting of N or O, tetrahydro-2H-pyran-4-yl, or morpholinyl; wherein D, E and F are independently and optionally substituted with one or more:  halo,  C₁₋₄alkyl, haloC₁₋₄alkyl, for example, F is heteroaryl, e.g., pyridyl substituted with one or more halo, haloC₁₋₄alkyl or C₁₋₄alkyl, or F is aryl, e.g., phenyl, substituted with one or more halo  or F is a C₃₋₇heterocycloalkyl optionally substituted with a C₁₋₆alkyl;  or e) a substituted heteroarylalkyl; f) attached to one of the nitrogens on the pyrazolo portion of Formula IV and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂ are independently H or halogen, and R₁₀ is:  halogen,  C₁₋₄alkyl,  C₃₋₇cycloalkyl,  C₁₋₄haloalkyl,  aryl,  heteroaryl, or  thiadiazolyl,  arylcarbonyl,  alkylsulfonyl,  heteroarylcarbonyl, or  alkoxycarbonyl; provided that when X Y, or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is not present; (xix) R₆ is H, C₁₋₄alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, arylC₁₋₄alkyl, arylamino, heterarylamino, N,N-diC₁₋₄alkylamino, N,N-diarylamino, N-aryl-N-(arylC₁₋₄alkyl)amino (e.g., N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or —N(R₁₈)(R₁₉); wherein the aryl or heteroaryl is optionally substituted with one or more halo, hydroxy or C₁₋₆alkoxy, (xx) n=0; (xxi) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are, independently H or C₁₋₄alkyl, aryl, heteroaryl, (optionally hetero)arylC₁₋₄alkoxy or (optionally hetero)arylC₁₋₄alkyl; (xxii) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl, (xxiii) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl; (xxiv) R₁₈ and R₁₉ are independently H, C₁₋₄alky or aryl wherein said aryl is optionally substituted with one or more halo or hydroxy, (xxv) R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl, (xxvi) R₂₁ is C₁₋₆alkyl; in free or salt form.
 8. The method of claim 1, wherein a PDE1 inhibitor is administered to a patient that is shown to have elevated intracellular calcium levels compared to a control subject.
 9. The method of claim 1, wherein the PDE1 inhibitor is the following compound:

in free or pharmaceutically acceptable salt form. 